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Role of lipid A palmitoylation in bacterial pathogenesis

Departments of Laboratory Medicine and Pathobiology, and Biochemistry, University of Toronto, Toronto, Ontario, Canada, russell.bishop{at}utoronto.ca

Sang-Hyun Kim

Departments of Laboratory Medicine and Pathobiology, and Biochemistry, University of Toronto, Toronto, Ontario, Canada

Ahmed El Zoeiby

Departments of Laboratory Medicine and Pathobiology, and Biochemistry, University of Toronto, Toronto, Ontario, Canada

The presence of palmitate in a minor fraction of lipid A has been known since the chemical structure of lipid A was first elucidated, but the functional importance in bacterial pathogenesis of regulated lipid A palmitoylation has become clear only recently. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP. The isolation of pagP mutants from pathogenic Gram-negative bacteria has revealed that palmitoylated lipid A can both protect the bacterium from certain host immune defenses and attenuate the ability of lipid A to activate those same defenses through the TLR4 signal transduction pathway. The mechanisms by which bacteria regulate the incorporation of palmitate into lipid A strikingly reflect the corresponding organism's pathogenic lifestyle. Variations on these themes can be illustrated with the known pagP homologs from Gram-negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is now lending itself both as a target for the development of anti-infective agents, and as a tool for the synthesis of lipid A-based vaccine adjuvants and endotoxin antagonists.

Key Words: Lipid A • palmitoylation • bacterial pathogenesis

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